Halogenated derivatives of aceto propane



Patented a. 15, 1940 UNITED STATES PATENT OFFICE- HALOGENATEDDERIVATIVES OF ACETO PRO PANE

Edwin RLBuchman, Pasadena, Calif, assignor to Research Corporation, NewYork, N. Y., a corporation of New York No Drawing.

6 Claims.

118.573 is a division of application Serial No.

98,929, which I filed September 1, 1936, while application Serial No.171,905 is a continuation in part of application Serial No. 11,683,which I filed March 18, 1935 and of said application Serial No. 98,929.In the foregoing applications the product obtained by halogenating-yaceto propyl alcohol or by hydrolysing halogenated a aceto vbutyrolactone is described as 7 halogen 7 aceto propyl alcohol but ithas been subsequently found that molecules of a 'y halogen 'yacetopropyl alcohol tend to react spontaneously with one another to formhalogenated aceto propyl ethers with surprising ease. These ethers whenin aqueous solutions hydrolize into the halogenated alcohol more or lesscompletely according to the concentration and temperature. When 'yhalogen 'y aceto propl alcohol is distilled, the resulting product mayconsist predominately of either the al-- cohol or the ether dependinguponthe temr perature, pressure and/or speed-oi the distillation. Theconditions fol-isolation described in the above mentioned applicationsare such as to produce, inwhole or in part, the ether rather than thealcohol.

There are three possible forms in which 7 acet'o propyl alcohol mayexist, the formulae-of \vhich may be written:

moc":om-cmcmon (ketonicform) (enolic form) Application Septembe SerialNo. 296,817

and

OH 7 HaC(g-CHr-CH:CH:

III

(inner other, laciono ring or tetrahydrolurane iorm) It is probable thatany solution of this product contains some or all of these formsinequilibrium. The above outlined keto'nic form undoubtedly is intautomeric equilibrium with the enolic form of the molecule. Thesetautomeric forms are, however, so readily interconvertlble, in harmonywith, enol-keto tautomers in general, that 'for the sake of simplicitythe enolic forms-will be ignored in the following discussion."

, 4 The several halogen derivatives of 'y aceto propyl alcohol likewisein having thestructures: p

O I .HtC -CHXCH2-CHIOH:

and 1 on HicJf-cHx-oHiom o in which X is one of the halogens chlorine,bromine and-iodine. It is obvious that when two molecules of one .ofthese halogenated aceto propyl alcohols react to form an ether, theresulting ether may have any one 013 the following structures:

x cocrn ay exist in similar 'forms in which formulae, X has the samesignificance as before. It is diflicult to determine which of tilstandpoint.

.embodiments thereof.

these forms the ether will assume under any given set of conditions, butit appears that the form usually obtained under ordinary conditions, asin the specific examples given hereinafter, possesses onetetrahydrofurane radical and has the structure indicated by FormulaVIII.

In the aforementioned application Serial No. 171,905, I have describedseveral methods of making halogen derivatives of aceto propyl alcoholand have described the properties of the resulting products. Severalproducts of reaction which boil over the range from 84 to C. at 1 to 2mm. pressure are described therein and, while halogen derivatives of 7aceto propyl alcohol undoubtedly are present in the reaction mixturesobtained by halogenation of 'y aceto propyl alcohol, one of the abovedescribed halogenated ethers is the rincipal product obtained upondistillation under the conditions described, instead of thecorresponding halogenated alcohol as stated in my previous applicationsreferred to hereinabove. However, for all practical purposes, thedesired result is obtained no matter which compound is secured becausein the presence of traces of water the ether reacts as if the alcoholwere used. For example, if the product is dissolved in water, a solutioncontaining halogenated aceto propyl alcohol is obtained. Since theprincipal intended use of the product is in the synthesis of thethiazole portion of vitamin B1 and in such synthesis water is present oris formed in the course of the reaction, the particular product isolatedis more or less immaterial except from a theoretical Because the etheris more stable than the alcohol, it is preferable from a practicalstandpoint to employ the ether.

In accordance with th present invention, a halogenated derivative ofaceto propane may be prepared by the halogenation of 'y aceto propylalcohol with one of the elemental halogens bromine, chlorine and iodineor with, sulphuryl bromide or sulphuryl chloride. The same halogenatedderivative may likewise be made by halogenating a aceto 'y butyrolactone with the same halogenating agent and then subjecting theresulting a halogenated butyrolactone to a combined hydrolysis anddecarboxylation. The reaction product is then treated in a suitablemanner to remove the desired product, or products, which may be ahalogen derivative of 'y aceto propyl alcohol, a halogen derivative ofaceto propyl ether, or both, depending upon the isolation process.

The invention will be fully understood from the following detaileddescription of specific As an example of how the invention may bepracticed, "y aceto propyl alcohol may be halogenated by treatment witha suitable halogenating agent, such as a halogen or a sulfuryl halide.

Example 1 In accordance with one specific embodiment of the invention, 7brom 'y aceto propyl alcohol which may also be designated3-brom-3-acetop'ropan-l-ol, may be prepared by dissolving 30 grams of 'yaceto propyl alcohol in cc. of water and vigorously stirring thesolution while- 48 grams of bromine are added drop by drop at such arate that the color imparted to the solution by one drop of the brominedisappears before the next drop is added. The aqueous solution whichresults contains impure 'y brom 'y aceto propyl alcohol.

One method of purifying the product is to separate the small amount ofinsoluble oil which is formed as a by-product, from the aqueous solutionand to extract the aqueous solution repeatedly with ordinary ethyl etherto dissolve the remainder of the brominated product. The insoluble oiland the ethereal extracts are combined and dried over a suitabledehydrating agent such as anhydrous sodium sulfate. The ethyl ether isthen distilled oil and the residue is practically pure di (brom acetopropyl) ether which is hereinafter designated brom aceto propyl ether.This material may be further purified, if desired, by distilling it invacuo at less than 1 mm. of mercury. The product is a colorless oil,which is soluble in hot water, ether and alcohol and which may bedistilled though not without some decomposition. The pure substance canbe readily distilled in a molecular still at 40 C. bath temperature andat 0.008 mm. pressure.

Calcd. for: CmI-IwOaBrz, mol. wt.=343.96; 0:34.89; H=4.69. Found: mol.wt.=316 (dioxane); C=34.84; H=4.56.

The brom aceto propyl ether thus prepared is sparingly soluble in waterbut freely soluble in organic solvents such as petroleum ether. It maybe converted into 7 brom 'y aceto propyl alcohol by making a dilutewater solution thereof, for it hydrolizes readily into the brominatedalcohol. The solution of the ether in water may be most readily effectedby mild heating at a temperature of 50 to 60 C The brom alcohol has notbeen isolated as such because it goes over into the ether too readily.However, the presence of the alcohol in a water solution of the bromether has been established by freezing point depression of the aqueoussolution.

Example 2 The corresponding chlorine derivatives may likewise be made bydirect reaction of chlorine upon 1 aceto propyl alcohol. This reactionmay be carried out by treating 12 grams of 'y aceto propyl alcohol,dissolved in 60 cc. of water, with a stream of gaseous chlorine, thereaction mixture beng stirred and cooled if necessary so that thetemperature remains between 20 C. and 40 C. This is continued until theincrease in weight of the reaction mixture reaches 8 grams, The mixtureis cooled to about 15 C. and allowed to stand 15 minutes during whichtime a small, heavy, oily layer separates at the bottom of the vessel.This oily layer is removed and washed twice with water. The aqueouslayer and the aqueous washings are extracted with ethyl ether. Then theethereal extracts are combined with the above oily layer and dried overa suitable dehydrating agent, such as sodium sulfate. The ethyl ether isevaporated oil leaving an oil boiling at 87 C. to 110 C. at about 2 mm.pressure. This material is a stable, colorless oil which is soluble inether, alcohol and hot water and is slightly soluble in cold water. Thisproduct consists principally of chlor aceto propyl ether having theproperties described in Example 5 below.

The invention also contemplates the production of the related iodinederivatives in a similar manner, although iodine is not so reactive asbromine or chlorine and the yield of the iodine 7 compounds is not sogreat.

Example 3 In practicing one process of this nature, 27 grams of sulfurylchloride are added slowly to 20.4 grams oi 7 aceto propyl alcohol andthe reactionmixture is kept at 0 C. for one-half hour. At the end ofthat time, 50 cc. of ethyl ether are added and the mixture is heated toexpel the sulfur dioxide and the hydrogen chloride remaining in themixture. The mixture is then cooled and poured onto crushed ice and theexcess acidity is neutralized with a potassium carbonate solution. Theresulting mixture is repeatedly extracted with petroleum ether and theether extract is treated first with anhydrous sodium sulfate and finallywith anhydrous potas sium carbonate. After the extract is dried, the.

residue is distilled'in vacuo to removethe petroleum ether and theresidue is iractionally distilled in vacuo, whereupon a product having aboiling point at 2 mm. pressure of about to 120 C. is obtained. Thisproduct also consists predominately of the aforementioned chlor acetopropyl ether.

The corresponding brom compounds may be prepared in a similar manner byreacting upon 7 aceto propyl alcohol with an equivalent amount ofsulfuryl bromide and purifying the product obtained by a similarprocedure.

The brom, chlor and iodo derivatives of aceto propane describedhereinbefore may also be made by simultaneously hydrolizing anddecarboxylating the corresponding a halogen derivative of a aceto vbutyro lactone. The a aceto 'y butyrolactone employed in this reactionhas the formula Chlor aceto propyl ether may be obtained by firstpreparing c: chlor a aceto 'y butyro lactone by treating a acto v butyrolactone with sulfuryl chloride, in accordance with the method describedin my aforesaid copending application Serial No. 118,573.

In carrying out this reaction 68 grams of the a aceto 'y butyrolactone'are placed in a flask equipped with a mechanical stirrer and 68 grams ofsulfuryl chloride are added with continual stirring over a period of oneand a half hours.

After the reaction is completed the recation product is washed withwater, taken up in ether and dried over a suitable dehydrating agent,such as calcium chloride. The ethereal extract is then distilled at areduced pressure and the fraction distilling at approximately 85 C. and2 or 3 mm. pressure is collected. This product is substan- C. for 75minutes. J chlor butyro lactone is simultaneously hydrolyzed theformula:

omoo CHr-CH:

81 grams of this chlor lactone, 80 cc. of water and 15 cc. ofconcentrated hydrochloric acld'are then mixed and heated under a refluxcondenser at and recarboxylated in accordance with the followingequation:

cmco our-0H,

A similar result is obtained by using a dilute solution-of an alkaliinstead of the dilute acid.

principally chlor aceto propyl ether and is substantially identical withthe product obtainedby direct chlorination of 1 aceto propyl alcohol anddistillation of the reaction product as described in Example 2. i I

Example 5 410 grams of the chlorinated lactone prepared as described inExample 4 are heated on a steam bath with 410 cc. of water and 12 cc. of38%.

hydrochloric acid until decarboxylation is complete. This operationrequires about 7 hours. On cooling the reaction mixture an oily layerseparates which is removed by repeated extraction of the mixture withpetroleum ether. The ether extracts arethen shaken with solid potassiumcarbonate to remove any acid, the potassium carbonate is filtered oif,the solvent is removed by means of a water pump and the remaining oil isfraction-ally distilled. The fraction boiling at 68 C. to 120 C. at apressure of 1 mm. is collected and upon redistillation of this fractionpure chlor aceto propyl ether is obtained from the distillate boiling atto 112 at l-mm. pressure. Calcd for CwHwOaClz: mol. wt.=255.06; 0:47.04;H=6.32; and 01:27.81. Found: mol. wt. 259 (dioxane); 0:47.14; H=6.13;and (11:28.07.

d 1.2175 gm./cc.; 12? 1.4748

This chlor aceto propyl ether is a colorless and almost odorless liquidwhich is soluble with difliculty in water but which is readily solublein organic solvents.

Example 6' If the oily liquid described in Example 5 is fractionallydistilled at 1.7 mm. pressure and that fraction which is obtained at 68to 70 C. is redistilled at 3 10-= mm. at 20 to 24 C., a fraction isobtained consisting of 'y chlor 'y aceto propyl alcohol. Calcd forC5H9O2C1; mol. wt. 136.54; C=43.95; H=6.64; and C1=25.96. Found:

tially pure or chlor a aceto 1 butyrolactone having 1 By this treatmentthe mol. wt.=146 (dioxane); C=44.64; H=8.29 and (71:26.43.

in a carbon dioxide trap. Thus, it is evident that both chlor acetopropyl alcohol and chlor aceto propyl ether may beobtained from the samereaction mixture and that the product isolated depends upon theconditions which exist during the isolation step.

Aqueous solutions of chlor aceto propyl ether give molecular weightvalues indicating complete hydrolysis into chlor aceto propyl alcohol.The ether goes into water solution readily when the mixtures are warmed,60 C. having proved to be asatislactory temperature to employ.

: Example 7 grams of chlor aceto propyl ether, prepared by any oi; theforegoing processes are heated with 500 cc. of 'water at 60 C. for aboutsix hours and themixture is allowed to stand. All of the resulting oilylayer will dissolve upon shaking the mixture. The mixture is extractedrepeatedly .with ether, the etherealextracts aredriedover a suitabledehydrating agent, such as sodium sullate, and the solvent is thenremoved in a water pump at 200? C. The residual oil is then fractionallydistilledinamolecular still and 'y chlor 7 aceto propyl alcohol, boilingat 27 C. at 0.01

mm. pressure is obtained. Calcd for Cal-190201;

moi. wt.=136.54; 0:43.95; H=6.64 and 01:25.97. Found: apparent mol.wt.=118.5; corrected for 'mol. of water consumed in the hydrolysis wouldgive mol. wt.=127.5; 0:44.35; H=6.48.

The chloraceto propyl alcohol is insoluble in petroleum ether, -whilechlor aceto propyl ether dissolves therein readily.

The bromine compound which corresponds to the chlorinated lactonedescribed hereinabove in Example 4 may be made in an analogous manner bytreating a aceto butyrolactone with sulphuryl bromide or in aqueoussuspension with bromine. The bromide compound corresponding to the abovedescribed chlorinated aceto propyl alcohol may then be prepared bytreating the brominated lactone with a suitable pH regulating agent,such as dilute hydrobromic acid.

' Example 8 These reactions may be carried out by suspending 32 grams ofa. aceto v butyrolactone in '70 cc. of water and adding 40 grams ofbromine thereto drop by drop, meanwhile vigorously stirring the mixturewith a mechanical stirrer. This will produce a bromo a aceto 'ybutyrolactone and in the reaction which occurs hydrobromic acid is alsoproduced. This brominated lactone may be hydrolyzed and decarboxylatedby means of a dilute solution of hydrobromic acid. Since hydrobromicacid is present in the reaction mixture resulting from the brominationof the lactone, the simplest way to hydrolyze the brominated lactone isto continue to stir the mixture after the bromine has been added, untilthe hydrolysis and decarboxylation are completed. The brominated productresulting from the hydrolysis is extracted from the mixture with ether,and the ethereal extract is dried. The dried extract is freed from ethylether and is then distilled in vacuo at about 1 mm. pressure and thebrom aceto propyl ether is collected. This material is an oil which iscolorless when freshly made, but it is not as stable as thecorresponding chlorine compound and darkens on standing. 1

The corresponding 7 iodo 'y aceto propyl alcohol and iodo aceto propylether may be produced in smaller yields than the related chlor and bromcompounds by employing elemental iodine instead of the chlorinating andbrominating agents mentioned previously in the several reactionsdescribed hereinabove. If desired, the iodo compounds may also beprepared in more substantial yields, bytreating one of the chlor or bromalcohols or ethers with sodium iodide.

As stated previously, the halogenated aceto propyl ethers obtained mayamume the structures indicated by Formulae VI, VII, and VL'J outlinedhereinabove. II VI were the correct structure, one would expect that twomolecules of phenyl hydrazine would react with 1 molecule of thedi-halo-aceto-propyl ether. If the correct structure were VII phenylhydrazine would not react with this ether at all. Actually in fullagreement with structure VIII only 1 molecule of phenyl hydrazine reactswith 1 molecule of the ether. When a second molecule of phenyl hydrazineispresent, it separates from the reaction mixture as phenyl hydrazinehydrochloride. The product of reaction of phenyl hydrazine with 'yhalogen v aceto propyl ether is analogous in structure to"tetraph'enyltetracarbazon" described by Sven Bodforss in Brichte derdeutschen chemischen Gesellschai't, vol. 52, p. 1762 and 1767 (1919) andvol. 72, p. 468 (1939). The reaction involved is also analogous to thatof Bodiorss, but only one side of the molecule undergoes reaction withphenyl hydrazine. Thus the product of the action of phenyl hydrazine on'y chloro 'y aceto propyl ether having the properties described inExample 5 is a yellowish crystalline powder melting at about 85 C.,insoluble in water or petroleum ether, but soluble in other usualorganic solvents, such as alcohol, acetone or ether. It has acomposition corresponding to the formula CraHarOaNzCl. According to thelater ideas of Bodform, its structure is as follows:

If an excess of phenyl hydrazine is used in the above reaction and aninert solvent is employed,

' "the excess of the reagent is unchanged showing the presence of oneand only one a. chlor keto group in the molecule of the 'y chloro 'yaceto propyl ether. This is further confirmed by the action of iodine onan aqueous alkaline solution of 'y chloro 'y aceto propyl ether. If thisreaction is carried out with a cold water solution only half as muchiodine is consumed as is thecase when the 'y chloro 'y aceto propylether is first warmed with water for a few minutes before carrying outthe iodine 'reaction. This is evidence that the ether has only one COCH3group and that another such group is formed when the ether is hydrolyzedinto the related alcohol.

From the foregoing. it is apparent that the halogenated aceto propylethers produced as described hereinbefore contain at least onetetrahydrofurane group and that in all probability they contain only onesuch group. However, the appended claims are intended to embrace allforms of the ether unless specifically limited to cover only certainones of such ethers.

The chlorine, bromine and iodine derivatives of 'y aceto propyl alcoholand ether produced in accordance with the invention may be condensedwith thio foramide to produce salts of the thiazole derivative known as-methyl-S-(B hydroxy ethyl) thiazole in accordance with the methodoutlined in Patent No. 2,133,966 granted October 25, 1938. This thiazolederivative may in turn be caused to enter into other reactions toproduce synthetic compounds having the characteristic physiological andtherapeutic properties of the antineuritic vitamin. e

What is claimed is:

1. The method which comprises simultaneously hydrolyzing anddecarboxylating an a halogen derivative of a aceto 1 butyro lactoue inwhich the halogen is a member of the group consisting of chlorine,bromine and iodine.

2. The method which comprises simultaneously hvdrolyzing anddecarboxylating a iodo a aceto 7 butyro lactone.

5. The method which comprises simultaneously hydrolyzing anddecarboxylating a chlor a aceto 'y butyro lactone by subjecting saidlactone to the action of a dilute solution of hydrochloric acid.

6. The method which comprises simultaneously hydrolyzing anddecarboxylating a brom a. aceto 1 butyro lactone by subjecting saidlactone to the action of a dilute solution of hydrobromic acid.

EDWIN R. BUCHMAN.

